title: Synthesis and in vivo evaluation of [(18)F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([(18)F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates.
abstract: The 5-HT1AR partial agonist PET radiotracer, [(11)C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki=0.1nM; Emax=77%; EC50=0.65nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [(18)F]fluoroethyltosylate in DMSO in the presence of 1.6equiv of K2CO3 in 45±5% yield (EOS). PET shows [(18)F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [(18)F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [(18)F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, Columbia University, 1051 Riverside Drive, Box #42, New York, NY 10032, United States.
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Milak
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: Pratap
authors.initials: P
authors.lastname: Mali
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Savenkova
authors.forename: Norman R
authors.initials: NR
authors.lastname: Simpson
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry; D010215:Papio; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C586766:((18)F)2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; D005462:Fluorine Radioisotopes; D010879:Piperazines; D019275:Radiopharmaceuticals; D058825:Serotonin 5-HT1 Receptor Agonists; D014227:Triazines; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT1AR; Agonist; Brain; FECUMI-101; PET; Radiotracer